Mucormycosis is a life-threatening infection that occurs in patients immunocompromised by diabetic ketoacidosis, neutropenia, corticosteroids, or organ transplantation. Because of the increasing prevalence of these risk factors, the number of patients at risk for this deadly infection is on the rise. Despite disfiguring surgery and aggressive antifungal therapy, the mortality of mucormycosis remains >50%, and it approaches 100% in patients with disseminated disease or neutropenia. Clearly novel strategies to prevent and treat mucormycosis are urgently needed. In the past decade new therapies have become available that have the potential to improve outcomes of mucormycosis. Recently we have made the exciting discovery that iron chelation has the potential to markedly improve the outcome of Rhizopus oryzae infection in vivo. Furthermore, we have found that dead R. oryzae is capable of mediating damage to human cells, suggesting the presence of a toxin-like substance in R. oryzae. New data indicate that such a toxin is likely produced by an endosymbiotic bacteria rather than the fungus itself, and that fluoroquinolones targeting those endosymbiotic bacteria may prove efficacious in treating mucormycosis. It is therefore hypothesized that a combination therapeutic strategy that attacks at least two distinct mechanistic targets in the fungus will result in greater efficacy than the current standard monotherapy regimen. We will determine the maximally effective antifungal strategy in both a hematogenously disseminated and inhalational model of murine mucormycosis. The primary endpoint will be time to death, and tissue fungal burden. Tissue concentrations of the drugs will be secondary endpoints. The in vitro activity of the combination therapies will be performed to correlate susceptibility with survival outcomes. These Specific Aims will define the optimal antifungal strategy for highly lethal mucormycosis infections in mice. Additionally, data obtained from these studies will lay the foundation for future R01s designed to elucidate the role of fungal viability, iron metabolism, and toxin production in the pathogenesis of this infection. Finally, the results of the current studies will be crucial to prioritizing antifungal strategies and study design for possible future clinical trials of patients infected with this extraordinarily deadly disease. [unreadable] [unreadable] [unreadable]